Alkoxy derivatives of pyrazolopyridine carboxylic acids and esters

ABSTRACT

NEW ALKOXY DERIVATIVES OR PYRAZOLO (4,3-C) PYRIDINE-7CARBOXYLIC ACIDS AND ESTERS HAVE THE GENERAL FORMULA   1-R1,3-R2,4-(R3-O-),7-(R-OOC-)PYRAZOLO(4,3-C)PYRIDINE   THEY ARE USEFUL AS ATARACTIC AGENTS. IN ADDITION, THE NEW COMPOUNDS INCREASE THE INTRACELLULAR CONCENTRATION OF ADENOSINE-3&#39;&#39;,5&#39;&#39;-CYCLID MONOPHOSPHATE.

United States Patent 3,763,172 ALKOXY DERIVATIVES OF PYRAZOLOPYRIDINECARBOXYLIC ACIDS AND ESTERS Theodor Denzel, Numberg, and Hans Hoehn,Tegeruheim, Germany, assignors to E. R. Squibb & Sons, Inc., Princeton,NJ. No Drawing. Filed Jan. 12, 1972, Ser. No. 217,295 Int. Cl. C07d31/36 US. Cl. 260-2955 B Claims ABSTRACT OF THE DISCLOSURE New alkoxyderivatives of pyrazolo[4,3-c]pyridine-7- carboxylic acids and estershave the general formula They are useful as ataractic agents. Inaddition, the new compounds increase the intracellular concentration ofadenosine-3,5'-cyclic monophosphate.

SUMMARY OF THE INVENTION This invention relates to new alkoxyderivatives of pyrazolo[4,3-0]pyridine-7-carboxylic acids, their estersand salts of these compounds as well as processes for producing them.These new compounds have the Formula R2H(\N N ll I'M COOR In Formula I,the alkyl groups represented by R are straight or branched saturatedhydrocarbon groups of up to 12 carbons. Preferred, however, are thelower alkyl groups of up to seven carbon atoms such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, amyl and the like.

Similar lower alkyl groups are represented by R R and also are part ofthe phenyl-lower alkyl substituents. The substituted benzoyl groupsinclude phenyl rings bearing one or two substituents. Thus R representsR R benzoyl wherein R and R each is hydrogen, halogen, especiallychlorine or bromine, lower alkyl or lower alkoxy, including benzoyl,chlorobenzoyl, e.g., 0-, mor p-chlorobenzoyl, bromobenzoyl, e.g., 0-,mor p-bromobenzoyl, o-, mor p-toluoyl, 2,5-dichlorobenzoyl, 3,5-dimethylbenzoyl, 3,4-dimethoxybenzoyl and the like. Unsubstituted andmonosubstituted benzoyl are preferred.

The new compounds of Formula I are produced by the following method.

ice

A S-aminoisoxazole of the formula II) R 2 [produced by reacting 3iminobutyronitrile with hydroxylamine by the procedure described in Ann.Chem.

624, 22 (1959)] is made to react with an alkoxymethylene malonic acidester of the formula alkO 011:0

COOR

wherein R is alkyl, by heating at a temperature of about The resultingcompound of the formula (IV) R I /CO0R N \O/NH--C. C

OOOR

is cyclized in an inert organic solvent, while distilling olf thealcohol formed, producing a compound of the formula This is thenalkylated by treatment with an alkyl halide in an inert organic solventlike dimethylformamide in the presence of an alkali metal carbonate toobtain a compound of the formula o N The 4-hydroxy compound of FormulaV, instead of being alkylated, may be refluxed for several hours with aphosphorus halide like phosphorus oxychloride to obtain the intermediateof the formula OOOR e.g., wherein R is hydrogen or lower alkyl, and R islower alkyl. Butylamine is preferred.

This reaction yields a compound of the formula (VIII) The compound ofFormula VIII is then hydrogenated with a catalyst like palladium oncharcoal in an organic solvent like acetic acid to form a compound ofthe formula Treatment of the compound of Formula IX with hydrazine orhydrazine hydrate yields a compound of the formula which may then bealkylated with about one equivalent of a lower alkyl halide orphenyl-lower alkyl halide R -X (X is a halogen, preferably iodine) in aninert organic solvent in the presence of an alkali metal carbonateproducing a compound of Formula I.

Products of Formula I in which R is other than hydrogen are producedfrom compounds of Formula I (R1=H) by alkylating with an additionalequivalent of an alkyl halide in the presence of an alkali metalcarbonate.

Products of Formula I in which R is hydrogen are produced from theesters by hydrolysis of the latter, e.g., with a base like sodiumhydroxide. The compounds of Formula I form salts which are also part ofthis invention. The salts include acid-addition salts, particularly thenon-toxic, physiologically acceptable members. The bases of Formula Iform salts by reaction with a variety of organic acids providing acidaddition salts including, for example, hydrohalides (especiallyhydrochloride and hydrobromide), sulfate, nitrate, borate, phosphate,oxalate, tartrate, malate, citrate, acetate, ascorbate, succinate,benzenesulfonate, methanesulfonate, cyclohexanesulfonate andtoluenesulfomate. The acid addition salts frequently provide aconvenient means for isolating the product, e.g., by forming andprecipitating the salt in an appropriate menstruum in which the salt isinsoluble, then after separation of the salt, neutralizing with a basesuch as barium hydroxide or sodium hydroxide, to obtain the free base ofFormula I. Other salts may then be formed from the free base by reactionwith an equivalent of acid.

The new compounds of this invention are central nervous systemdepressants and may be used as tranquilizers or ataractic agents for therelief of anxiety and tension states, for example, in mice, cats, rats,dogs and other mammalian species, in the same manner aschlordiazepoxide. For this purpose a compound or mixture of compounds ofFormula I, or non-toxic, physiologically acceptable acid addition saltthereof, may be administered orally or parenterally in a conventionaldosage form such as tablet, capsule, injectable or the like. A singledose, or preferably 2 to 4 divided daily doses, provided on a basis ofabout 1 to 50 mg. per kilogram per day, preferably about 2 to mg. perkilogram per day, is appropriate. These may be conventionally formulatedin an oral or parenteral dosage form by compounding about 10 to 250 mg.per unit of dosage with conventional ve-= hicle, excipient, binder,preservative, stabilizer, flavor or the like as called for by acceptedpharmaceutical practice.

The new compounds also increase the intracellular concentration ofadenosine-3',5-cyclic monophosphate, and thus by the administration ofabout 10to 50 mg./kg., in single or two to four divided doses inconventional oral or parenteral dosage forms such as those describedabove may be used to alleviate the symptoms of asthma.

4 r The following examples are illustrative of the invention. Alltemperatures are on the centigrade scale.

EXAMPLE 1 4-ethoxy-3 -methylpyrazo- [4, 3 -c pyridine-7-carboxylic acidethyl ester (a) [[(3 methyl 5 isoxazolyl)amino]inethylene]' malonic aciddiethyl ester: 112.5 g. of 3-methyl-5-aminoisoxazole (1.14 mol.) and 248g. of ethoxymethylene malonic acid diethyl ester (1.14 mol.) are heatedwith stirring for 45 minutes at 130. After this period, ethanol isremoved under reduced pressure. The residue solidifies on cooling and isrecrystallized from ethanol, M.P. 134- 136,yield 245 g.

(b) 4 hydroxy 3 methylisoxazolo[3,4-b1pyridine- S-carboxylic acid ethylester: 50 g. of [[3-methyl-5-isox-. azolyl) amino]methylene]malonic aciddiethyl ester (0.19 mol.) are quickly added to 250 m1. of vigorouslyrefluxing diphenyl ether. After 7 minutes, the reaction mixture iscooled rapidly. The solvent is" distilled off in vacuo and the oilyresidue crystallizes after adding 100 ml. of methanol. Recrystallizationfrom methanol yields 20 g. (48%) of 4 hydroxy 3methylisoxazolo[3,4-b]pyridine-5- carboxylic acid ethyl ester, M.P.150-152.

(c) 4 ethoxy 3-methylsioxazolo[3,4-b]pyridine-5-carboxylic acid ethylester: 22.2 g. of4-hydroxy-3-methylisoxazolo[3,4-b]pyridine-S-carboxylic acid ethyl ester(0.1 mol.) are dissolved in 150 ml. of ethanol and 28 g. of potassiumcarbonate (0.2 mol.). 31 g. of ethyl iodide (0.2 mol.) are added. Themixture is heated with stirring for 6 hours. The hot solution isfiltered and the solvent evaporated. The oily residue yields oncrystallization with meth-' anol 18.2 g. of4-ethoxy-3-methyl-isoxazolo[3,4-b]pyridine-S-carboxylic acid ethyl ester(73% M.P. 62

(d) 4 butylamine 3-methylisoxazolo[3,4-b]pyridine- S-carboxylic acidethyl ester: 25 g. of .4-ethoxy-3-methylisoxazolo[3,4-b] pyridine 5carboxylic acid ethyl ester (0.113 mol.) are dissolved in 100 ml. ofbenzene and after adding 8 g. of butylamine (0.23 mol.), the solution isrefluxed for 12 hours. The solvent is distilled oif and the residual 4butylamine-3-rnethylisoXazolo[3,4b]pyridine- S-carboxylic acid ethylester is recrystallized from ligroin, M.P. 60, yield 23.5 g.

(e) 3 acetyl 4-butylamino-2-hydroxypyridine-S-carboxylic acid ethylester: 300 g. of 4-butylamino-3-methylisoxazolo[3,4 b] pyridine 5carboxylic acid ethyl ester (1.08 mol.) are dissolved in 0.5 liter ofacetic acid, 1 g. of palladium on charcoal is added and the mixture ishydrogenated. After absorption of 24 liters of hydrogen, the reaction isstopped, the catalyst is filtered off and the solvent removed in vacuo.The residue is treated for 7 hours at with 0.5 liter of water withstirring. The reaction mixture is cooled and extracted 3 times with 200ml. portions of chloroform. The organic layers are col lected, driedover sodium sulfate and evaporated to dr ness. Recrystallization of theoily residue yields 216 g. of 3acetyl-4-buty1amino-2-hydroxypyridine-5-carboxylic acid ethyl ester (72%M.P. 134136.

(f) 4 hydroxy 3-methyl-lH-pyrazolo[4,3-c]pyridine- 7-carboxylic acidethyl ester: 8.4 g. of 3-acetyl-4-butyl amino 2hydroxypyridine-S-carboxylic acid ethyl ester (0.03 mol.) are dissolvedin 20 ml. of acetic acid, 3 ml. of hydrazine hydrate are added and themixture is refluxed for 5 hours. After this time, the solvent is removedin vacuo and the crystalline precipitate for 4-hydroxy-3- methyl 1Hpyrazolo[4,3-c]pyridine-7-carboxylic acid ethyl ester is recrystallizedfrom acetic acid, yield 5.1g. (77%), M.P. 310.

(g) 4 ethoxy '3 methyl 1H pyrazolo[4,3-c]pyridine-7-carboxylic acidethyl ester: 2.2 g. 4-hydroxy-3- methyl 1Hpyrazolo[4,3-c]pyridine-7-carboxylic acid ethyl ester (0.01 mol.) 2.8 g.of potassium carbonate, (0.02 mol.) and 1.6 g. of ethyl iodide aresuspended in 50 ml. of dimethylformamide and heated for 10 hours at w nWhat is claimed is:

1. compound of the formula I: O-Ra T C) h (50 O R 10 wherein is hydrogenor alkyl of up to 125 carbon atoms, R is hydrogen, lower alkyl, metaorpara- R R -benzoyl, phenyl, benzyl or phenethyl, R is hydrogen, loweralkyl,; phenyl, benzyl or jphenethyl, R is low'er"all;yl, benzyl orphenethyl, R and R each is hydrogenQhzilogen, methyl or methoxy, andphysiologically acceptable acid addition salts thereofi Y 2. A compoundas inc'laim 1 wherein'R, R andflR each is lower alkyl and R is hydrogen.g 3. A compound as in claim 1 wherein RandR each is ethyl, R ismethyland R1 is hydrogen. r

4. A compound as in claim 1 wherein R, R R and R each is lower alkyl. 4j 3 g 5. A compound as in claim 1 whereinRand R each 25 is ethyl, R isethyl, and R i is methyl. .7

References Cited I f UNITED STATES PATENTS? 3,669,950 6/1972 Hoehn eta1. j 2 6o '-295.5 B OTHER REFERENCES 7 v a Roberts et al., BasicPrinciples of Organic Chemistry, Benjamin Publishers, Page 806, 1965 Q1?251 R 58 C6 35 ALAN L. ROTMAN, Primary Examiner I a I Us; 01. X.R.260-2955 R, 294.8 R; 424-466 5 w w m m m m ammo ammo WHO Lemovfio E6emov mo :maaifi E0 E6. E0 moxficv E6 E6 H6 H0 J "N m i A SH oawwwn um mmaUmHz O

